- Functional Disruption of the Cancer-Relevant Interaction between Survivin and Histone H3 with a Guanidiniocarbonyl Pyrrole Ligand
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The protein Survivin is highly upregulated in most cancers and considered to be a key player in carcinogenesis. We explored a supramolecular approach to address Survivin as a drug target by inhibiting the protein–protein interaction of Survivin and its fu
- Aschmann, Dennis,Bayer, Peter,Beuck, Christine,Ehlers, Martin,Giese, Michael,Killa, Matthias,Knauer, Shirley K.,Meiners, Annika,Mertel, Marcel,Schmuck, Carsten,Vallet, Cecilia
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Read Online
- Elastase Inhibitor Cyclotheonellazole A: Total Synthesis and in Vivo Biological Evaluation for Acute Lung Injury
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Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is one of the most common complications in COVID-19. Elastase has been recognized as an important target to prevent ALI/ARDS in the patient of COVID-19. Cyclotheonellazole A (CTL-A) is a nat
- Chen, Yue,Cui, Yingjun,Deng, Yangping,Fu, Qiang,Jiang, Peng,Li, Jing,Lin, Jianping,Liu, Yang,Meng, Qing,Sun, Yuanjun,Wang, Liang,Wang, Mukuo,Xu, Honglei,Ye, Baijun,Zhang, Mengyi,Zhang, Songming,Zhang, Tingrong,Zhao, Xiuhe
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- PYRROLOBENZODIAZEPINE DIMER PRECURSOR AND LIGAND-LINKER CONJUGATE COMPOUND THEREOF
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The present invention relates to a pyrrolobenzodiazepine dimer prodrug and a ligand-linker conjugate compound thereof, a composition containing these, and therapeutic use thereof particularly as an anticancer drug. The stability of the compounds themselves and the stability thereof in plasma are excellent and the compounds are advantageous in terms of manifestation of toxicity, and thus the compounds are industrially useful in that it is possible to target proliferative diseases such as cancer, to perform a specific treatment, to maximize the drug efficacy, and to minimize the occurrence of side effects.
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- Antibody-drug conjugate with acidic self-stabilizing joint
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The invention provides a special hydrophilic acidic stable joint-drug conjugate. The acidic stable joint is introduced, so that conjugate has relatively high drug loading capacity in comparison with conjugate with relatively low drug loading capacity, i.e., each targeted reagent has higher number of hydrophilic drug joints; and meanwhile, expected PK properties are kept, and same or better activity can be achieved in vivo.
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Paragraph 0113; 0114; 0115; 0116
(2018/09/14)
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- Phosphate bioisostere containing amphiphiles: A novel class of squaramide-based lipids
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We describe a novel class of amphiphiles with squaramide moiety as a phosphate bioisostere. Most synthesized squaramide-based amphiphiles have the favorable physicochemical properties of lipids, such as: formation of stable liposomes or giant unilamellar vesicles in aqueous solution, high phase-transition temperature, low vesicle leakage and phospholipase resistance properties.
- Saha, Abhishek,Panda, Subhankar,Paul, Saurav,Manna, Debasis
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p. 9438 - 9441
(2016/07/29)
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- Synthesis of a series of ω-dimethylaminoalkyl substituted ethylenediamine ligands for use in enantioselective catalysis
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The title compounds H2NCH((CH2)nNMe2)CH2NH2 L1-L4 (n = 1-4) are efficiently synthesized in enantiopure form. The commercial starting materials, l-asparagine, (S)-5-hydroxymethyl-2-pyrrolidinone, and (S)-6-(((benzyloxy)carbonyl)-amino)-2-((tert-butoxycarbonyl)amino)hexanoic acid, are elaborated in 6-9 standard steps to give L1 (18% overall), L2 (13%), L3 (36%) and L4 (38%) or the corresponding tris(hydrochloric acid) salts [H3NCH((CH2)nNHMe2)CH2NH3]3+ 3Cl-, which are preferable for long term storage. The sequences make use of isobutyl carbamate, Cbz, and Boc protecting groups and Hofmann type rearrangements; the dimethylamino groups are introduced at late stages, either via reductive dimethylations or nucleophilic displacements involving mesylates and HNMe2. L1-L4 chelate to [Co(en)2]3+ fragments to give octahedral complexes that catalyze numerous enantioselective reactions.
- Ghosh, Subrata K.,Ganzmann, Carola,Gladysz, John A.
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p. 1273 - 1280
(2015/11/09)
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- THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE
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Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.
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Page/Page column
(2015/02/19)
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- THERAPEUTICALLY ACTIVE COMPOUNDS AND USE THEREOF
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Provided are therapeutically active compounds and the use in manufacture of medicaments for treating a cancer characterized by the presence of a mutant allele of IDH1.
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Page/Page column 72; 73
(2015/02/19)
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- THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE
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Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.
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Page/Page column 72
(2015/02/19)
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- Sulfate Encapsulation in Supramolecular Structures from L -Asparagine-Derived 2,5-Diketopiperazine Scaffolds: Anion Binding
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We report a new sulfate receptor, anchored onto 2,5-diketopiperazine units, which results in the formation of two types of supramolecules; one in which the sulfate ion guest fits snugly into extended cavities and the other in which the guest is sandwiched between layers. In each case, the anion is held by six hydrogen bonds from the host. 1H NMR spectroscopic solution studies enabled the construction of Job plots, and calculation of stoichiometry and association constants. These findings are of possible significance in drug design and for construction of combinatorial libraries.
- Naini, Santhosh Reddy,Lalancette, Roger A.,Gorlova, Olga,Ramakrishna, Kallaganti V. S.,Yadav, Jhillu Singh,Ranganathan, Subramania
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p. 7015 - 7022
(2016/02/19)
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- Benzimidazole analogs of l-tryptophan are substrates and inhibitors of tryptophan indole lyase from Escherichia coli
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Tryptophan indole lyase (TIL), an enzyme found in Escherichia coli and related enterobacteria, produces indole from l-tryptophan (l-Trp). Indole is a signaling molecule in bacteria, affecting biofilm formation, pathogenicity and antibiotic resistance. β-(Benzimidazol-1-yl)-l-alanine (BZI-Ala), 2-amino-4-(benzimidazol-1-yl)butyric acid (homo-BZI-Ala) and 2-amino-5-(benzimidazol-1-yl)pentanoic acid (bishomo-BZI-Ala) were synthesized and tested as substrates and inhibitors of TIL. BZI-Ala is a good substrate of TIL, with Km = 300 μm, kcat = 5.6 s-1 and kcat/Km = 1.9 × 104, similar to l-Trp. BZI-Ala is also a good substrate for H463F mutant TIL, which has very low activity with l-Trp. In contrast, homo-BZI-Ala was found to be a potent competitive inhibitor of TIL, with a Ki of 13.4 μm. However, the higher homolog, bishomo-BZI-Ala, was inactive as an inhibitor of TIL at a concentration of 600 μm, and is thus a much weaker inhibitor. The reaction of TIL with BZI-Ala was too fast to be observed in the stopped-flow spectrophotometer, and shows an aldimine intermediate in the steady state. However, H463F TIL shows equilibrating mixtures of aldimine and quinonoid complexes in the steady state. The spectra of the reaction of TIL with homo-BZI-Ala show a rapidly formed intermediate absorbing at 340 nm, probably a gem-diamine, that decays slowly to form a quinonoid complex absorbing at 494 nm. The potent binding of homo-BZI-Ala may be due to it being a 'bi-product' analog of the indole-α-aminoacrylate complex. These results demonstrate that an amino acid substrate may be converted to a potent inhibitor of TIL simply by homologation, which may be useful in the design of other potent TIL inhibitors. β-(Benzimidazol-1-yl)-l-alanine (BZI-Ala), 2-amino-4-(benzimidazol-1-yl) butyric acid (homo-BZI-Ala), and 2-amino-5-(benzimidazol-1-yl)pentanoic acid (bishomo-BZI-Ala) were synthesized and tested as substrates and inhibitors of tryptophan indole-lyase (TIL), an enzyme found in Escherichia coli and related enterobacteria. BZI-Ala is a good substrate of TIL, homo-BZI-Ala is a potent competitive inhibitor of TIL, with Ki of 13.4 μM, but bishomo-BZI-Ala, was inactive as an inhibitor of TIL. 2013 The Authors Journal compilation
- Harris, Austin P.,Phillips, Robert S.
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p. 1807 - 1817
(2013/06/05)
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- THERAPEUTICALLY ACTIVE COMPOSITIONS AND THEIR METHODS OF USE
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Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.
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(2013/07/31)
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- THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE
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Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.
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Page/Page column 71; 72
(2013/07/31)
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- On-bead screening of a combinatorial fumaric acid derived peptide library yields antiplasmodial cysteine protease inhibitors with unusual peptide sequences
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A new class of cysteine protease inhibitors based on fumaric acid derived oligopeptides was successfully identified from a high-throughput screening of a solid-phase bound combinatorial library. As target enzymes falcipain and rhodesain were used, which play important roles in the life cycles of the parasites which cause malaria (Plasmodium falciparum) and African sleeping sickness (Trypanosoma brucei rhodesiense). The best inhibitors with unusual amino acid sequences not reported before for this type of enzyme were also fully analyzed in detail in solution. Ki values in the lower micromolar and even nanomolar region were found. Some inhibitors are even active against plasmodia and show good selectivity relative to other enzymes. Also the mechanism of action was studied and could be shown to be irreversible inhibition.
- Machon, Uwe,Buchold, Christian,Stempka, Martin,Schirmeister, Tanja,Gelhaus, Christoph,Leippe, Matthias,Gut, Jiri,Rosenthal, Philip J.,Kisker, Caroline,Leyh, Matthias,Schmuck, Carsten
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scheme or table
p. 5662 - 5672
(2010/03/24)
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- Chemoenzymatic and chemical routes to the nonproteinaceous amino acid albizziine and its amide derivative
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A two-step route for the synthesis of albizziine from Na-Boc-asparagine which proceeds in 65% overall yield is disclosed. A high-yielding, six-step route for the synthesis of its protected amido derivative gives rapid access to a key component of the complex aminopolyol natural product, zwittermicin A. Georg Thieme Verlag Stuttgart.
- Dobrovinskaya, Nina A.,Archer,Hulme, Alison N.
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p. 513 - 516
(2008/12/21)
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- Synthetic pores with sticky π-clamps
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In this report, we describe design, synthesis, evaluation and molecular dynamics simulations of synthetic multifunctional pores with π-acidic naphthalenediimide clamps. Experimental evidence is provided for the formation of unstable but inert, heterogeneo
- Tanaka, Hiroyuki,Bollot, Guillaume,Mareda, Jiri,Litvinchuk, Svetlana,Tran, Duy-Hien,Sakai, Naomi,Matile, Stefan
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p. 1369 - 1380
(2007/12/26)
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- ETHER DERIVATIVE
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The present invention relates to an ether derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof wherein each symbol is as defined in the description, and an ether derivative represented by the formula (III), a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof wherein each symbol is as defined in the description; a pharmaceutical composition containing the ether derivative; and a package containing the pharmaceutical composition and a description of use thereof. A pharmaceutical composition of the present invention, which contains this compound of the present invention has a superior anti-inflammatory and analgesic activity and is useful as various pharmaceutical agents such as an anti-inflammatory agent, an analgesic, a therapeutic agent for inflammatory bowel disease, a therapeutic agent for pollakiuria and/or incontinentia, a therapeutic agent for asthma and the like.
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Page/Page column 35
(2008/06/13)
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- An Efficient Synthesis of a Probe for Protein Function: 2,3-Diaminopropionic Acid with Orthogonal Protecting Groups
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(Matrix presented) An efficient and cost-effective synthesis of N(α)-Boc2-N(β)-Cbz-2,3-diaminopropionic acid is reported. The synthesis starts from commercially available N(α)-Boc-Asp(OBn)-OH and employs a Curtius rearrangement to establish the β-nitrogen. Proper protection of the α-nitrogen is essential for the success of the Curtius rearrangement.
- Englund, Ethan A.,Gopi, Hosahudya N.,Appella, Daniel H.
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p. 213 - 215
(2007/10/03)
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- Homochiral 4-azalysine building blocks: Syntheses and applications in solid-phase chemistry
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Anomalous amino acids not only play central roles as mimics of natural amino acids but also offer opportunities as unique building blocks for combinatorial chemistry. This paper describes the chiral syntheses and solid-phase applications of a versatile atypical amino acid, 4-azalysine (2,6-diamino-4-azahexanoic acid) 1. The syntheses of differentially protected 4-azalysine derivatives 28a-e have been developed by two efficient and inexpensive routes that start either from Garner's aldehyde 16 or the chiron (S)-Nα-Cbz-2,3-diaminopropionic acid 23. Both approaches employ the convergent modular concept and exploit reductive amination of aldehydes with amines as the key step for the fusion of the two segments. In the first route, the overall process inverts the chirality of the starting material, L-serine, and thus provides an excellent route to the unnatural D-isomers. The alternative route starting from L-asparagine provides a shorter and high-yielding route to orthogonally protected 4-azalysine derivatives. The corresponding N2-Fmoc-4-azalysines 31a-e, readily derived from the key intermediate 27, are compatible with the Fmoc-based solid-phase peptide synthesis (SPPS) and solid-phase organic chemistry (SPOC) protocols. Furthermore, the utility and versatility of another key structure, tris-Boc-4-azalysine 2 in the engineering of novel high-loading dendrimeric polystyrene resins 33 and 36, have been demonstrated. Following derivatization with the Rink amide linker 34, the stability and robustness of these resin-bound dendrimers 35 and 37 in the synthesis of small molecules using a range of reaction conditions (e.g., Mitsunobu and Suzuki reactions) have been effectively illustrated.
- Chhabra, Siri Ram,Mahajan, Anju,Chan, Weng C.
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p. 4017 - 4029
(2007/10/03)
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- Synthesis of dipeptide-bound epoxides and α,β-unsaturated amides as potential irreversible transglutaminase inhibitors
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Herein we report the synthesis of 24 novel peptides as potential irreversible inactivators of transglutaminase (TGase). These peptides were designed to resemble Cbz-L-Gly, known to be a good TGase substrate, and to include either α,β-unsaturated amide groups or the corresponding epoxide groups. The side chain length of the amino acid residue bearing the inhibitor group was also varied in order to permit investigation of this effect. Copyright
- De Macedo, Pierre,Marrano, Claudio,Keillor, Jeffrey W
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p. 355 - 360
(2007/10/03)
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- Facile chemical syntheses of porphobilinogen analogues: A four-step synthesis to iso-porphobilinogen
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iso-Porphobilinogen was prepared in four good yielding steps, as well as a group of iso-porphobilinogen analogues, using a modification of Zav'yalov's method.
- Cheung,Shoolingin-Jordan
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p. 1627 - 1630
(2007/10/03)
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- Synthesis of (R)- and (S)-2,3-diaminopropyl sulfate: Mechanism based inhibition of glutamate 1-semialdehyde aminomutase
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A short synthesis of each enantiomer of 2,3-diaminopropyl hydrogensulfate is described starting from (2R)- and (2S)-asparagine. The compounds serve as inhibitors for pyridoxal 5'-phosphate-dependent (2S)- glutamate 1-semialdehyde aminotransferase, a target for selective herbicides and antibacterial agents on the tetrapyrrole biosynthetic pathway. The (2R)- enantiomer, as predicted, serves as a potent irreversible inactivator. (C) 2000 Elsevier Science Ltd.
- Khayer, Khurshida,Jenn, Thierry,Akhtar, Mahmoud,John, Robert,Gani, David
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p. 1637 - 1641
(2007/10/03)
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- Synthesis of alanine and proline amino acids with amino or guanidinium substitution on the side chain
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Competitive binding of peptides containing basic amino acids to disrupt or prevent the Tat-TAR interaction could result in diminished transcription as well as translation and hence constitutes an alternative way of controlling HIV replication. Therefore, we synthesized guanidinium and amino containing amino acids, based on a proline or an alanine scaffold. The introduction of the guanidinium moiety was best accomplished using 1H- pyrazole-1-carboxamidine hydrochloride, with Pmc used for its protection. The absence of racemization, maintained throughout the whole synthesis, was confirmed by chiral purity determination. These building blocks were smoothly incorporated into oligopeptides, which proved their suitability for use in a combinatorial approach for selecting TAR binding ligands. (C) 2000 Elsevier Science Ltd.
- Zhang, Zhenyu,Aerschot, Arthur Van,Hendrix, Chris,Busson, Roger,David, Frank,Sandra, Pat,Herdewijn, Piet
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p. 2513 - 2522
(2007/10/03)
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- Synthesis of novel, orthogonally protected multifunctional amino acids
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Two synthetic strategies for the generation of differentially protected, chiral tri-amino acids have been developed. The first strategy is based on the reductive amination of a serine-derived oxazolidine aldehyde with mono N- protected ethylenediamine. The second approach involves reductive alkylation of an asparagine-derived N-protected diaminopropionate with an N-protected glycinal. The newly generated secondary amine functionality is derivatised to furnish structurally diverse molecules.
- Chhabra, Siri Ram,Mahajan, Anju,Chan, Weng C.
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p. 4905 - 4908
(2007/10/03)
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- 2,3-diaminopropionic acid derivative
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The present invention relates to a 2,3-diaminopropionic acid derivative of the formula (1): STR1 or a pharmaceutically acceptable salt thereof. The compounds of the present invention are useful as a platelet aggregation inhibitor, a cancer metastasis inhibitor, a wound healing agent or a bone resorption inhibitor.
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- Rearrangement of Nα-Protected L-Asparagines with Iodosobenzene Diacetate. A Practical Route to β-Amino-L-alanine Derivatives
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A general synthetic method for the Hofmann rearrangement of protected asparagines has been developed. Reaction of asparagine derivatives with iodosobenzene diacetate (PIDA) in mixed solvents produces β-amino-L-alanines in good yield. Advantages over the commonly used reagent bis(trifluoroacetoxy)iodobenzene have been discussed.
- Zhang, Lin-Hua,Kauffman, Goss S.,Pesti, Jaan A.,Yin, Jianguo
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p. 6918 - 6920
(2007/10/03)
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- Reaction of Trimethylsilylamines with N-Cbz-L-Serine-β-Lactone: A Convenient Route to Optically Pure β-Amino-L-alanine Derivatives
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Trimethylsilylamines, Me3Si-NR2, react with N-Cbz-L-serine-β-lactone in acetonitrile primarily by alkyl oxygen cleavage of the lactone ring to give optically pure N-Cbz-β-amino-L-alanine derivatives in good yields.Use of halogenated sovents such as chloro
- Ratemi, Elaref S.,Vederas, John C.
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p. 7605 - 7608
(2007/10/02)
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- Metal Chelating Amino Acids in the Design of Peptides and Proteins. Synthesis of Nα-Fmoc/But Protected Amino Acids Incorporating Aminodiacetic Acid Moiety.
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The synthesis of Fmoc/But protected amino acid chelators 14, 15, 16 and 24 is described.With respect to their Boc/Bzl derivatives, the title compounds offer synthetic advantage: peptide Ac-Ada(1)-Ala3-Ada(1)-Ala4-Glu-Lys-NH2 was assembled by So
- Kazmierski, Wieslaw M.
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p. 4493 - 4496
(2007/10/02)
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- A Simple Conversion of Alkohols into Amines
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In a convenient one-pot sequence, treatment of alcohols and α-hydroxyesters with hydrazoic acid, di-isopropyl azodicarboxylate and an excess of triphenylphosphine in tetrahydrofuran, followed by addition of water or aqueous acid, yields amines or amino-acid esters in moderate to good overall yields.
- Fabiano, Emmanuel,Golding, Bernard T.,Sadeghi, Majid M.
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p. 190 - 192
(2007/10/02)
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- Synthesis of N2-Protected L-2,3-Diaminopropanoic Acids
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The title compounds have been synthesized from N-protected L-aspartic acid via Curtis rearrangement.
- Noguchi, Noriyoshi,Kuroda, Tsuyoshi,Hatanaka, Minoru,Ishimaru, Toshiyasu
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p. 633 - 634
(2007/10/02)
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